The long-term goal of this project is to develop hyperpolarized MRI methods for the prediction and characterization of chronic obstructive pulmonary disease (COPD), a prevalent pulmonary disorder that is projected to become the third leading cause of death in the U.S. by 2020. Recent publications, including our, suggest that hyperpolarized gas MRI techniques are uniquely sensitive to the early onset of COPD in both human subjects and animal models. Our approach has been to develop noninvasive hyperpolarized MRI techniques to detect this disease in its early stages and to identify new therapeutic agents. During the first funding cycle we designed and implemented various methods to accurately measure regional alveolar partial pressure of oxygen, ventilation, perfusion, and ventilation-to-perfusion ratio, as well as oxygen depletion rate and diffusivity of helium-3 in the lung. We have evaluated the utility of these regional parameters in the quantitative assessment of lung function and structure. The most exciting results are: 1) significant changes in regional ventilation in emphysematous lungs that precede histological findings;2) significant changes in the regional partial pressure of oxygen and regional ventilation-to-perfusion ratio in lungs with perfusion defects;3) an elevated value of regional apparent diffusion coefficient of helium-3 in emphysematous lungs that correlates well with histology;4) design and fabrication of a state-of-the-art programmable ventilator capable of delivering an accurate mixture of oxygen, nitrogen, and hyperpolarized helium-3 to both small and large animals;5) development of hyperpolarized carbon-13 technology for the quantitative measurement of regional perfusion. These methods were developed in animal models and have now been translated to clinical use at several sites to comprehensively assess lung function and structure. However, these non-invasive methods have not, as yet, been used to characterize the underlying mechanisms of emphysema. The objectives of the current proposal are to use these non-invasive hyperpolarized helium-3 MRI parameters for studying the underlying mechanisms that lead to the development of emphysema. Specifically, we will 1) induce emphysema in a rat model using chronic exposure to cigarette smoke;2) trace the progression of emphysematous changes with hyperpolarized helium-3 MRI markers, established CT parameters, pulmonary function tests, and histology;3) measure the regional concentration of the molecular signatures of apoptosis and identify the onset of the disease through hyperpolarized helium-3 markers;and 4) further the understanding of disease pathogenesis and evaluate possible interventions in emphysema progression by disrupting specific apoptosis pathways We will employ a number of sophisticated and novel methods, including hyperpolarized helium-3 MRI parameters to quantitatively assess lung function and immunohistological staining methods to measure molecular signatures responsible for apoptosis in lung tissue, to achieve these goals.